Alzheimer?s disease (AD) is the most prevalent neurodegenerative disease of aging, with one in eight older Americans diagnosed with AD. It is also the most frequently diagnosed type of dementia within the Veterans Affairs (VA) Medical System, and one of the major causes of morbidity and mortality among veterans. The Department of VA estimates that 600,000 veterans suffered from severe AD and other forms of dementia in 2000, and this number is increased significantly today, because of the increasing proportion of older veterans and the increased prevalence of dementia in veterans that suffer from traumatic brain injury (TBI) and/or post- traumatic stress disorder (PTSD). Therefore, AD research studies are particularly important to veterans. Currently no treatment is available to slow or stop AD. There is a great need for identification of more efficacious therapies for AD, which is among the priorities of VA RR&D research directions. Synaptojanin 1 (synj1), the main phosphoinositol biphosphate phosphatase [PIP2 degrading enzyme] in the brain and synapses, has been recently linked to AD. More importantly, we have demonstrated that synj1 regulates lysosomal clearance of A? and that the increased synj1 expression links to ApoE4-induced phospholipid dysregulation and cognitive deficits. Down-regulation of synj1 promotes A? clearance, reduces tau hyper-phosphorylation and ameliorates ApoE4 pathogenic effects. Subsequently, reduction of synj1 attenuates AD-related pathological changes and behavioral deficits in AD mouse models. These findings suggest that reduction of synj1 has potential therapeutic benefits for AD. Our initial screening of 89 top hits out of a library of compounds (~3,600 small molecules) with the potential to reduce synj1 protein levels using ?The Connectivity Map?, identified a FDA-approved drug nimodpine with synj1- and A?-lowering effects in both wild- type and ApoE4 neuronal cultures. Further administration of nimodipine for one month, is capable of reducing brain content of synj1 and A?, as well as improving cognitive functions in an AD transgenic mouse model and an ApoE4 KI mouse model. However, chronic administration of nimodipine failed to reduce brain A?42 levels (particularly insoluble fractions), or to improve cognitive function. Our data suggest that the effects of nimodipine on reduction of synj1 expression are independent of its inhibitory effects on calcium channel activities. We then designed and synthesized first-generation nimodipine structural analogs using medicinal chemistry to reduce its calcium channel activity, and identified a novel compound, SynaptoCpd#9, with attenuated inhibition of calcium channels and increased potency against synj1 and A?42 compared to nimodipine both in vitro and in vivo. Oral administration of SynaptoCpd#9 in APPSwe/PS1?E9 and ApoE4 mice for 3-6 months improved cognitive function and reduced AD-related pathologies (insoluble A?42 particularly). RNA-sequencing and qPCR studies of treated ApoE4 neurons identified three candidate genes involved in nimodipine- or SynaptoCpd#9-mediated effects. We posit that continued exploration of SAR of nimodipine derivatives and further dissection of their mechanisms of actions will provide new insights regarding AD pathogenesis and may lead to identification of novel targets for AD therapies. In this application, we propose to refine structural modifications of nimodipine derivatives to increase their potency at lowering synj1 and improving cognitive function in AD mouse models (aim 1: medicinal chemistry modifications, in vitro test funnel assays and in vivo proof of concept animal studies). In parallel studies, we propose to dissect mechanisms of actions of these novel compounds (aim 2: mechanistic studies), which will provide new insights regarding mechanisms of AD pathogenesis and advance therapeutic strategies for AD. Information obtained from our proposed studies will lead to development of novel potent AD therapies, and better understanding of AD pathogenesis through mechanistic investigation. Therefore, our studies will directly benefit Veterans, and improve the quality of service provided within the VA health care system.